The present invention relates to a method of and an apparatus for testing membrane filters, and an apparatus for sterilizing liquids with use of a membrane filter.
A filtration process for sterilizing liquids with use of membrane filters is needed for preparing injection solutions and other liquid pharmaceuticals or for sterilizing industrial water. This process requires testing of the membrane filter for perfection and removal of air from the filter housing. To carry out the liquid sterilizing filtration process automatically, the automation of the filter perfection test and the deaeration of the filter housing is essential, but extreme difficulties are encountered in automating these steps as will be described later.
A description will be given of the conventional sterilizing filtration process for pharmaceutical liquids, especially membrane perfection test and filter housing deaeration.
First in a substerilization chamber, a medicinal liquid is sent from a preparation container through a filter for rough filtration into a primary receptacle (container) which has been cleaned and sterilized. On the other hand, a secondary receptacle (container) cleaned for containing the sterilized filtrate and a filter housing are placed into a sterilization chamber through a sterilizer provided between the substerilization chamber and the sterilization chamber. The filter housing has enclosed therein a cartridge membrane filter and is provided with tubes connected to the primary side and the secondary side of the fitler.
The membrane filter is tested for perfection in the sterilization chamber. The bubble point test (hereinafter referred to as "BPT") standardized according to ASTM-F316-70 is widely used as a method of testing membrane filters without entailing breaking or contamination and with ease and good reproducibility. According to BPT, the pores of the filter are regarded as capillary tubes, and the maximum radius of the pores is determined by measuring pressure, based on the relationship between the pressure and the maximum pore radius expressed by the equation (I) of surface tension given below. Conventionally this test is carried out in the following manner. First, the primary-side tube of the filter housing is connected to a gas source, such as an air, nitrogen or carbon dioxide source, via an indicating pressure gauge and a ball valve, while the forward end of the secondary-side tube of the housing is placed into water in a container. Prior to testing, the filter is impregnated with a liquid, such as distilled water, to fill the filter pores with the liquid by capillarity. With the valve opened to a suitable extent, the primary side of the filter is gradually pressurized with the gas. While checking the housing for leakage with the unaided eye, the operator observes the pressure gause and the end of the secondary-side tube. While the gas pressure applied to the primary side of the filter is relatively low, the pressure remains in an equilibrium with the liquid in the filter pores, so that the displacement of the liquid from the pores is negligible. When the pressure reaches a level, the liquid in large pores is forced out from the pores toward the primary side: This can be recognized from bubbles released from the end of the secondary-side tube. The pressure at this time is taken as bubble point pressure (hereinafter referred to as "BP pressure"). The relationship between this pressure P and the maximum radius r of filter pores is expressed by the following surface tension equation (I): EQU r=k(2.sigma. cos .theta./P) (I)
where .sigma. is surface tension, .theta. is contact angle, and k is a shape correction factor. Accordingly the filter pore size can be calculated from the BP pressure measurement as above. With the above method, however, it is necessary for the operator to observe the pressure gauge and the tube end at all times until the secondary-side tube releases bubbles and to read the pressure upon the release of bubbles. The procedure is therefore very cumbersome and involves extreme difficulties in automation. Further apparatus proposed for automatically testing membrane filters for perfection include one which is adapted to measure the rate of flow of diffused gas toward the secondary side of the filter when a pressure of about 80% of the BP pressure is applied to its primary side, or one which is adapted to detect the BP pressure reached by intermittently applying pressure to the primary side of the filter and measuring the variations in the pressure. The former apparatus nevertheless has the problem that the measurement varies with the filtering area of the filter and involves a greater error in the case of smaller filters. The latter apparatus has the problem that the measuring condition differs with the capacity of the housing. In either case, the delicate test condition setting needed renders the apparatus complex, expensive and difficult to maintain. Further although the test itself is conducted automatically, the acceptability of the filter as to its perfection must be determined by the operator based on the measurement. Accordingly it is extremely difficult to incorporate such a conventional apparatus into a line as an in-line filter testing apparatus.
When the perfection test for the membrane filter is completed, the primary-side tube of the filter housing is passed through the wall between the substerilization chamber and the sterilization chamber and is connected to the primary receptacle in the former chamber, and the secondary tube is connected to the secondary receptacle in the sterilization chamber to remove air from the housing, i.e. to discharge air from the primary side of the filter to ensure the filtering area of the filter. This is done by sending the medicinal liquid from the primary receptacle to the primary side of the housing, with the upper end of the housing held open. When the medicinal liquid is sent to the primary side of the housing, the air therein is discharged from the upper end of the housing, allowing the liquid level to gradually rise within the housing. While observing the liquid level, the operator closes the housing upper end upon the liquid level passing over the filter to complete deaeration. Thus, it is necessary for the operator to observe the liquid level within the housing at all times also during deaeration, so that the procedure is cumbersome and very difficult to automate.
After the filter housing is completely deaerated, the medicinal liquid is passed from the primary receptacle to the secondary receptacle continuously through the filter within the housing thus deaerated, whereby the liquid is sterilized by filtration.
When the medicinal liquid in one primary receptacle is completely filtered in this way, the primary and secondary receptacles are disconnected from the tubes of the filter housing. The secondary receptacle containing the sterilized liquid is carried to a filling machine within the sterilization chamber for filling. Before other primary and secondary receptacles are used for sterilizing medicinal liquid, membrane filter perfection test and filter housing deaeration must be carried out manually as above. The medicinal liquid may be sterilized and filled at the same time with use of a buffer tank connected to the filling machine, in place of the secondary receptacle. Even in this case, the membrane filter perfection test and filter housing deaeration must be conducted manually as above every time the liquid in one primary receptacle has been sterilized.